Diabetes mellitus is a major health problem directly affecting as many as 5% of the entire population in the U.S.A. The etiology of diabetes mellitus has been extensively investigated in experimental animals and humans. However, the basic mechanisms for the induction of diabetes is not fully understood. Since there is preliminary evidence that immune mechanisms might be involved in the induction of diabetes, I propose to study immunological aspects of the mechanism of induction of diabetes. When the mice are injected repeatedly with a low dose of streptozocin (40 mg per kg body weight daily for 5 days) hyperglycemia appears 5 to 7 days after the last injection. There is evidence that the induction of diabetes by this protocol is mediated by immunological mechanisms. The proposed studies will test this hypothesis. I will investigate the following areas: 1. I propose to determine the cellular basis for the induction of diabetes in experimental animals by repeated injections of a low dose of streptozotocin. 2. I propose to determine if diabetes is passively transferable to normal syngeneic mice with spleen cells from diabetic mice in which diabetes had been induced by repeated injections of streptozotocin. I plan to identify the cellular basis for such transfer. 3. I propose to investigate genetic influences on the induction of diabetes by repeated doses of streptozotocin. 4. Studies on the influence of sex hormones on the induction of diabetes by streptozocin are proposed. 5. Studies are proposed to test the hypothesis that anti-insulin receptor autoantibidies are involved in the pathogenesis in spontaneously diabetic mice. The proposed studies should provide a better understanding of the role of immunologic mechanisms in the pathogenesis of diabetes.